A pri-miR-218 variant and risk of cervical carcinoma in Chinese women

MicroRNA (miRNA)-related single nucleotide polymorphisms (SNPs) may compromise miRNA binding affinity and modify mRNA expression levels of the target genes, thus leading to cancer susceptibility. However, few studies have investigated roles of miRNA-related SNPs in the etiology of cervical carcinoma.

R E S E A R C H A R T I C L E Open Access

carcinoma in Chinese women

Ting-Yan Shi1,5, Xiao-Jun Chen2,5, Mei-Ling Zhu1,5, Meng-Yun Wang1,5, Jing He1,5, Ke-Da Yu3,5, Zhi-Ming Shao1,3,5, Meng-Hong Sun4,5, Xiao-Yan Zhou4,5, Xi Cheng2,5, Xiaohua Wu2,5*and Qingyi Wei1,6*

Abstract

Background: MicroRNA (miRNA)-related single nucleotide polymorphisms (SNPs) may compromise miRNA binding affinity and modify mRNA expression levels of the target genes, thus leading to cancer susceptibility However, few studies have investigated roles of miRNA-related SNPs in the etiology of cervical carcinoma

Methods: In this case–control study of 1,584 cervical cancer cases and 1,394 cancer-free female controls, we

investigated associations between two miR-218-related SNPs involved in the LAMB3-miR-218 pathway and the risk of cervical carcinoma in Eastern Chinese women

Results: We found that the pri-miR-218 rs11134527 variant GG genotype was significantly associated with a

decreased risk of cervical carcinoma compared with AA/AG genotypes (adjusted OR=0.77, 95% CI=0.63-0.95,

P=0.015) However, this association was not observed for the miR-218 binding site SNP (rs2566) on LAMB3 Using the multifactor dimensionality reduction analysis, we observed some evidence of interactions of these two SNPs with other risk factors, especially age at primiparity and menopausal status, in the risk of cervical carcinoma

Conclusions: The pri-miR-218 rs11134527 SNP was significantly associated with the risk of cervical carcinoma in Eastern Chinese women Larger, independent studies are warranted to validate our findings

Keywords: Case–control study, Cervical cancer, LAMB3-miR-218 pathway, Polymorphism, Genetic susceptibility

Background

nu-cleotide (nt) long endogenous noncoding RNAs that

regulate the mRNA expression of numerous target genes

[1] Disregulation of these target genes could alter

bio-logical processes as a result of either degradation of

tar-get mRNAs or repression of their translation by miRNA

binding to their 30-untranslated regions (UTRs) [2]

Accumulated data have shown that the deregulation of

miRNAs is involved in cell differentiation, proliferation,

apoptosis and carcinogenesis [3] MiRNAs include

pri-mary (pri-), precursor (pre-) and mature miRNA, in

which single nucleotide polymorphisms (SNPs) of these

miRNAs or in their binding sites on their target genes

may compromise miRNA binding affinity and change

mRNA expression levels of the target genes, thus leading

to cancer susceptibility [4,5] Several recent studies have indicated that miRNA-related SNPs, especially those located at miRNA binding sites or miRNAs themselves, can remarkably alter the biogenesis and/or function of the corresponding miRNAs and thus the risk of human cancers [4,6]

Cervical carcinoma is the third most commonly diagnosed cancer and the fourth leading cause of cancer

(529,800) of the new cancer cases and 8% (275,100) of the cancer deaths among women in 2008 [7] More than 85% of these cases and deaths occur in developing coun-tries, including China [7] Invasive cervical cancer can

be divided into two major histological types of squamous cell carcinoma (SCC) and adenocarcinoma, and SCC accounts for about 85% of the cases [8,9] A large body

of research in molecular epidemiology supports the hy-pothesis that persistent infection with oncogenic human papillomavirus (HPV), especially high-risk HPV types, is

* Correspondence: docwuxh@hotmail.com ; qwei@mdanderson.org

2 Department of Gynecologic Oncology, Fudan University Shanghai Cancer

Center, Shanghai, China

1 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China

Full list of author information is available at the end of the article

© 2013 Shi et al.; licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and

the primary cause of cervical carcinoma, deemed as a

necessary cause for the disease [7,10]

Recent studies have found that the expression levels of

miR-218 were associated with infection of high-risk

HPV involved in the pathogenesis of cervical cancer

[11] Specifically, in high-risk HPV16-positive cell lines,

the upregulation of E6 oncoprotein could reduce the

miR-218 expression; in contrast, the RNA interference

and was involved in tumor microenvironment by

in-creasing carcinoma cell migration [13] Others reported

the process of high-risk HPV infection and thus

contrib-ute to cervical carcinogenesis However, its intrinsic

mechanisms are still unclear It is likely that miRNAs

and related genetic variations may have effects on cancer

development [6] To date, only two reported studies

miRNA-related SNPs and the risk of cervical carcinoma

[6,14], two of which (i.e., pri-miR-218 rs11134527 and

LAMB3 rs2566) are found to be associated with altered

risk of cervical cancer in a Chinese Han population [6]

To further test the hypothesis that miRNA-related SNPs

cervical cancer risk, we performed a case–control study

with a much larger sample size to validate the reported

associations with cervical cancer risk in Eastern Chinese

women

Methods

Study subjects

The study population consisted of 1,584 cervical

carcin-oma patients, who had been operated between February

2008 and March 2011 in Fudan University Shanghai

Cancer Center (FUSCC) The tumors were

histopatho-logically confirmed independently as primary cervical

carcinoma by two gynecologic pathologists as routine

diagnosis at FUSCC An additional 1,394 cancer-free

fe-male controls were enrolled from women who had come

to the Outpatient Department of Breast Surgery at

FUSCC for breast cancer screening and agreed to

par-ticipate in this study These female controls, with the

selection criteria including no individual history of

cancer, were genetically unrelated and frequency

matched to the cases on age (± 5 years) and

residen-tial areas in Eastern China

During an in-person survey, all potential subjects were

interviewed to identify their willingness to participate in

this study As a result, a response rate for the cases and

controls was of approximate 95% and 95%, respectively Because the vast majority of Chinese women are non-smokers and non-drinkers, our study populations were restricted to women who did not smoke cigarettes or drink alcohol For the cases, detailed clinico-pathologic information was extracted from the patients0 electronic database of FUSCC, including tumor histology [15], FIGO stage (International Federation of Gynecology and Obstetrics, 2009), tumor size (i.e., the size of the primary tumor was the largest tumor diameter), pelvic lymph node (LN) metastasis, lympho-vascular space invasion (LVSI), depth of cervical stromal invasion and the ex-pression of estrogen receptor (ER) and progesterone re-ceptor (PR) Each participant provided a one-time 10 ml

of venous blood sample (after the diagnosis and before the initiation of treatment for the cases), and samples were kept frozen till DNA extraction for genotyping All samples were obtained from tissue bank of FUSCC The research was approved by the Institutional Review Board

of FUSCC, and a written informed consent was obtained from all recruited individuals Each clinical investigation was conducted according to the principles expressed in the Declaration of Helsinki consent

SNP selection and genotyping

The SNPs were selected from the NCBI dbSNP data-base (http://www.ncbi.nlm.nih.gov/projects/SNP) and the International HapMap Project database (http://hapmap ncbi.nlm.nih.gov/) based on four criteria: 1) located at

Han populations, 3) with low linkage disequilibrium by using anr2

threshold of < 0.8 for each other, and 4) pre-dicted as potentially functional SNPs by SNP function prediction (FuncPred) software from National Institute

of Environmental Health Sciences (http://snpinfo.niehs.nih gov/snpfunc.htm) As a result, only two reported SNPs (i.e., pri-miR-218 rs11134527 and LAMB3 rs2566) were selected, becausepri-miR-218 rs11134527 was predicted to be

from the whole blood, and the Taqman assay was per-formed for genotyping, as described previously [16,17] Four negative controls (without DNA template), duplicated positive controls and eight repeat samples were included in each 384-fomate for the quality control As a result, the mean genotyping rate was 99.3%, and the discrepancy rate

in all positive controls (i.e., duplicated samples, overlapping samples from previous studies and samples randomly selected to be sequenced) was less than 0.1%

Multifactor dimensionality reduction (MDR) analysis

To further explore high-order gene-environment inter-actions that were individually involved in cervical cancer

risk, we performed the MDR analysis, as described

pre-viously [17,18] This approach was used to find the main

factor and the combination of multiple factors (in this

case, SNPs and environmental risk factors) that were

significantly associated with cancer risk As a result,

the model that minimized the prediction error and

maximized the cross-validation consistency (CVC) was

chosen To reduce the probability of bias, we used

differ-ent random seeds to repeat the complete analysis for 10

times, and permutated the status of cases and controls

in the data set then repeated the test 1000 times under

the null hypothesis of no association This analysis was

performed by using the MDR V2.0 beta 8.2 program

(http://www.multifactordimensionalityreduction.org/)

Statistical analysis

The differences in selected variables between cervical

carcinoma cases and female controls were evaluated by

the Pearson'sχ2

-test The associations of genotypes with

the risk of cervical carcinoma were estimated by

com-puting odds ratios (ORs) and their 95% confidence

inter-vals (CIs) from both univariate and multivariate logistic

regression models, with or without adjustment for age,

age at primiparity, menopausal status and body mass

index (BMI) [19] The associations of SNP genotypes

with cervical carcinoma risk were also stratified by

demographic and clinico-pathologic variables We also

performed homogeneity test and logistic regression

ana-lysis to estimate and compare the risks between the

strata and interactions between two factors, respectively

For all significant genetic effects observed in our study,

we calculated the false-positive report probability (FPRP)

with prior probabilities of 0.0001, 0.001, 0.01, 0.1 and

0.25 to test for false-positive associations [20] A FPRP

value < 0.2 was considered a noteworthy and indicated a

remained robust association for a given prior probability

Statistical power was estimated to detect an OR of 1.50/

0.67 (for a risk/protective effect), with an α level equal

to the observedP value [20] All statistical analyses were

performed with SAS software (version 9.1; SAS Institute,

two-sided with a significance level ofP < 0.05

Results

Among all studied subjects, 19 cases and three controls

failed to be genotyped after repeated assays Thus, the

final analysis included 1,565 cases and 1,391 controls As

showed in Additional file 1: Table S1, there were no

sig-nificant differences in the distributions of age between

the cases and the controls with similar mean ages

of 45.8 (± 9.8) and 46.1 (± 8.9) years, respectively

(P=0.226) The cases were more likely to be

,

63.2% vs 51.0%) than the controls Because the differ-ences in age at primiparity, menopausal status and BMI were significant between cases and controls (all P<0.001), these variables were further adjusted for any residual confounding effect in later multivariate logistic regression analyses

The genotype frequencies of thepri-miR-218 rs11134527 andLAMB3 rs2566 SNPs as well as their associations with the risk of cervical carcinoma are summarized in Table 1 All observed genotype distributions in the 1,391 controls agreed with the Hardy-Weinberg equilibrium (HWE, P=0.083 and 0.094 for rs11134527 and rs2566, respectively)

In the recessive genetic model, thepri-miR-218 rs11134527 variant GG genotype was significantly associated with a decreased risk of cervical carcinoma compared with the

AA and AA/AG genotypes (adjusted OR=0.79 and 0.77, 95% CI=0.63-0.99 and 0.63-0.95, P=0.039 and 0.015, re-spectively) However, this association was not observed for

In stratification analyses, as showed in Table 2, under

a recessive genetic model, a decreased cervical

GG genotype was more evident in women who were younger at primiparity (≤ 24 yr, adjusted OR=0.73, 95%

observed for subgroups of SCC, FIGO stage I, stage II, positive pelvic LN, positive LVSI, deep cervical stromal invasion (> 1/2) and negative expression of ER and PR (P=0.008, 0.008, 0.028, 0.002, 0.008, 0.022, 0.011 and 0.014, respectively) However, homogeneity tests sug-gested that there was no difference in risk estimates between the strata (Table 2), and no statistical evidence for interactions between the genotypes and these vari-ables on the risk of cervical carcinoma (Additional file 1: Table S2)

We calculated the FPRP values for all the observed significant associations When the assumption of prior probability was 0.1, the association with thepri-miR-218

subgroups of premenopausal, SCC, FIGO stage I and positive pelvic LN (FPRP=0.189, 0.111, 0.163 and 0.153, respectively) (Additional file 1: Table S3)

rs11134527 variant could alter the local second structure

online tool that is an online RNA secondary structure prediction software based on the minimum free energy

to G (Figure 1)

Moreover, using the MDR analysis and including these two SNPs and three risk factors, we found that age at

primiparity was the best one-factor model with the

high-est CVC (100%) and the lowhigh-est prediction error (43.2%)

among all five discrete factors Intriguingly, the

five-factor model had a maximum CVC (100%) and a

mini-mum prediction error (38.6%), which showed a better

prediction than one factor (Table 3)

Discussion

In this relatively large hospital-based case–control study of

1,584 cervical cancer cases and 1,394 cancer-free female

controls, we validated two previously reported significant

pathway for the risk of cervical carcinoma in Chinese

popu-lations [6] We found that thepri-miR-218 rs11134527

vari-ant GG genotype was significvari-antly associated with a

decreased risk of cervical carcinoma compared with the

AA and AA/AG genotypes, and our sample size had a

stat-istical power of 94.9% to detect such an association Further

RNAfold prediction analysis showed a MFE changed from

−182.5 kcal/mol to −126.0 kcal/mol, when the nucleotide at

indicating that this variant may act as a functional SNP,

which affects the miRNA binding process and contributes

to cervical cancer susceptibility However, for the other

SNP (i.e.,LAMB3 rs2566), our data did not have statistical

evidence to support its association with cervical cancer risk

Our sample size had 100% statistical power to detect an

OR of 1.57 that was reported by Zhou et al [6] The

study and ours may be caused by differences in selection of subjects, different catchments of the hospitals and residen-tial regions as well as different sample sizes

Recent studies have demonstrated that miRNAs may function as tumor suppressors and/or oncogenes in human cancers [21,22], because elevated or decreased expression of miRNAs has been found in various tumor types, which may alter the regulation of mRNA expres-sion It is of note that miRNAs regulate gene expression

by the sequence-specific binding to the target mRNA, and these binding processes may be affected by SNPs located in the miRNA complementary site [23] There-fore, it is important to understand the functional and evolutionary significance of related genetic variations in determining expression of miRNAs and mRNAs that interact with each other as well as with environmental risk factors in the related biological processes [23,24]

It is well known that genetic variants may modify can-cer risk associated with environmental factors Although there were no two-factor interactions between geno-types and environmental factors, using the MDR analysis [18], we further explored high-order mul-tiple-factor interactions in associations with cervical cancer risk and found that age at primiparity was the strongest risk predictor among all the risk fac-tors considered Meanwhile, the interaction between the variant genotypes and other risk factors appeared

Table 1 Logistic regression analysis of associations between genotypes of theLAMB3-miR-218 pathway and cervical cancer risk

Variants

Genotypes

pri-miR-218 rs11134527

LAMB3 rs2566

OR, odds ratio; CI, confidence interval.

* χ 2 test for genotype distributions between cases and controls;

** Adjusted for age, age at primiparity, menopausal status, BMI in logistic regression models;

a

for dominant genetic models;

b

for recessive genetic models.

The results were in bold, if P < 0.05.

Table 2 Stratification analysis for associations between genotypes of theLAMB3-miR-218 pathway and cervical cancer risk in the recessive genetic model

Age, years

≤46 (Mean) 747/623 136/131 0.84 (0.64-1.11) 0.215 0.364 774/669 109/85 1.02 (0.74-1.40) 0.919 0.740

Age at primiparity, years

≤24 (Mean) 797/568 136/131 0.73 (0.56-0.96) 0.022 0.452 822/625 111/74 1.12 (0.82-1.54) 0.482 0.460

Menopausal status

Premenopausal 962/685 164/155 0.73 (0.57-0.94) 0.013 0.425 986/743 140/97 1.00 (0.75-1.34) 0.981 0.635

BMI, kg/m2

< 25 1026/759 175/157 0.79 (0.62-1.00) 0.054 0.715 1061/810 140/106 1.00 (0.75-1.32) 0.973 0.739

Histology

CINIII 129/1150 32/241 1.06 (0.68-1.66) 0.789 0.169 137/1233 24/158 1.32 (0.80-2.16) 0.274 0.409

Non-squamous 138/1150 23/241 0.75 (0.46-1.22) 0.240 138/1233 23/158 1.18 (0.71-1.96) 0.526 FIGO stage

Tumor size, cm

< 4 801/1150 139/241 0.78 (0.61-0.99) 0.043 0.695 840/1233 100/158 0.88 (0.66-1.16) 0.365 0.100

Pelvic LN

Negative 965/1150 174/241 0.83 (0.66-1.04) 0.098 0.095 1002/1233 137/158 1.00 (0.77-1.29) 0.970 0.819

LVSI

Negative 750/1150 132/241 0.80 (0.63-1.02) 0.073 0.305 783/1233 99/158 0.93 (0.70-1.24) 0.632 0.379

Depth of cervical stromal invasion

≤ 1/2 584/1150 99/241 0.75 (0.57-0.98) 0.037 0.898 598/1233 85/158 1.08 (0.81-1.45) 0.602 0.709

ER expression

Negative 647/1150 102/241 0.71 (0.55-0.92) 0.011 0.146 671/1233 78/158 0.85 (0.62-1.15) 0.289 0.365

PR expression

Negative 677/1150 110/241 0.73 (0.56-0.94) 0.014 0.407 703/1233 84/158 0.87 (0.65-1.18) 0.370 0.836

OR, odds ratio; CI, confidence interval; BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics; CIN, cervical intraepithelial neoplasia; SCC, squamous cell carcinoma; LN, lymph node; LVSI, lympho-vascular space invasion; ER, estrogen receptor; PR, progesterone receptor.

* Logistic regression models with adjustment for age, age at primiparity, menopausal status and BMI;

** Homogeneity test.

The results were in bold, if P < 0.05.

to modify the risk of cervical carcinoma, with the

five-factor model being the best model

MiR-218, is encoded by an intron of the SLIT2 tumor

suppressor gene [25], is known to be associated with the

development and progression of several cancers [21,22]

The decreased level of themiR-218 expression has been

observed in cancers of the breast, ovary, lung and

stom-ach [22,26,27], and its low expression level was also

cor-related with tumor stage, LN metastasis and poor

prognosis in gastric cancer [27] Recently, Martinez et al

reported a decreased expression level of miR-218 (> 2

fold) in HPV-16 or 18 positive cervical cancer cell lines

(i.e., SiHa, CaSki and HeLa) as well as in cervical tumor

tissues [12] They also demonstrated miR-218 as a spe-cific cellular target of high-risk HPV types [12], suggest-ing that the down-regulation ofmiR-218 is likely linked

to the process of HPV-associated tumorgenesis Based

on the Microcosm Targets tool software (http://www.ebi

found to have an effect on the mRNA expression regula-tion through more than 900 target genes, including LAMB3 [12], RICTOR [28], ROBO1 [27] and BIRC5 [29], that may play important roles in cervical carcino-genesis These genes were reported to participate in a number of cancer signaling pathways, such as the Wnt/ β-catenin, ERK/MAPK and Notch pathways [30] Laminin-5 has been found as a sensitive marker of early invasion of cervical lesions [31] LAMB3 that expressed

in many epithelial tissues could induce carcinogenesis by increasing carcinoma cell migration and disturbing tumor

ex-pression levels of the HPV16 E6 oncoprotein in cervical cancer cells and this process might be mediated by

miR-218 [12], which indicates a possible mechanism of the LAMB3-miR-218 pathway involved in the development of cervical carcinoma

It is known that the mRNA secondary structure is crit-ical for mRNA-miRNA interactions and gene functions [32] To investigate whether thepri-miR-218 rs11134527 SNP could alter the local second structure of the pri-miR-218 mRNA, we performed the RNAfold prediction analysis and found an obviously changed mRNA struc-ture from rs11134527 allele A to G These findings further suggest that germline genetic variations of pri-miR-218, such as rs11134527, may lead to an alteration

process and thus are associated with cervical cancer susceptibility

Several limitations of our study need to be addressed Firstly, this hospital-based case–control study may have selection bias and information bias, which may be mini-mized by frequency-matching cases and controls as well

as the adjustment for potential confounding factors in the final analyses Secondly, only two miR-218-related

Figure 1 The secondary structures of the pri-miR-218 mRNA.

These structures were predicted by inputting two 801-nt long

pri-miR-218 DNA sequences centering the rs11134527 locus into

RNAfold, with either (a) the rs11134527-A or (b) rs11134527-G allele.

The figures and the values of minimum free energy were generated

by RNAfold (http://rna.tbi.univie.ac.at).

Table 3 MDR analysis for the cervical cancer risk prediction with and withoutLAMB3-miR-218 pathway genotypes

Number of risk

factors

Best interaction models by MDR analysis

Cross-validation

Average prediction

test

5 age at primiparity, menopausal status, BMI,

rs11134527, rs2566

MDR, multifactor dimensionality reduction.

in pri-miR-218 and the other in miR-218 binding site)

were investigated in this study Cancer is a complex and

multifactorial disease, and any single SNP may not be

sufficient for the prediction of the overall risk [33]

Fu-ture studies should include more genes and more SNPs,

especially functional ones, associated with cervical

can-cer risk Finally, we did not have enough information on

other risk factors, especially HPV infection This was

be-cause the hospital did not perform HPV and related

sub-type detection for the diagnosis of all cervical cancer

cases, let alone for the female controls A recent

meta-analysis found that high-risk HPV16, 18 and 45 types

accounted for a greater or equal proportion of HPV

infections in cervical cancer, but not other high-risk

HPV types, such as HPV33, 51 and 58 [34] Therefore,

HPV types could be confounders in estimating the risk

associated with genetic factors

Conclusions

In summary, in the current case–control study of 1,584

cases and 1,394 controls, we found that the pri-miR-218

rs11134527 SNP was associated with the risk of cervical

carcinoma in Eastern Chinese women Our findings

sug-gest some possible interactions between genetic

other risk factors for cervical carcinoma However,

well-designed prospective studies with larger sample sizes are

required to validate our findings

Additional file

Additional file 1: Table S1 Distributions of selected variables in

cervical cancer cases and cancer-free female controls Table S2.

Interactions between genotypes of the LAMB3-miR-218 pathway and

environmental factors on cervical cancer risk Table S3 False-positive

report probability values for associations between genotypes of the

LAMB3-miR-218 pathway and cervical cancer risk.

Abbreviations

miRNA: microRNA; nt: Nucleotide; UTR: Untranslated region;

pri-miRNA: Primary miRNA; pre-pri-miRNA: Precursor miRNA; SNP: Single nucleotide

polymorphism; SCC: Squamous cell carcinoma; HPV: Human papillomavirus;

LAMB3: Laminin 5 β3; FUSCC: Fudan University Shanghai Cancer Center;

FIGO: International Federation of Gynecology and Obstetrics; LN: Lymph

node; LVSI: Lympho-vascular space invasion; ER: Estrogen receptor;

PR: Progesterone receptor; MAF: Minor allele frequency; MDR: Multifactor

dimensionality reduction; CVC: Cross-validation consistency; OR: Odds ratio;

CI: Confidence interval; BMI: Body mass index; FPRP: False-positive report

probability; HWE: Hardy-Weinberg equilibrium; MFE: Minimum free energy.

Competing interests

The authors declare that they have no competing interests.

Authors ’ contributions

Conception and design: QW, XW In-person survey and data collection: XJC,

XC, KDY, ZMS, MHS Genotyping and Provision of study materials: TYS, MLZ,

MYW, JH, XYZ Data analysis and interpretation: TYS, QW Manuscript writing:

TYS, QW, XW Final approval of manuscript: TYS, XJC, MLZ, MYW, JH, KDY,

ZMS, MHS, XYZ, XC, XW, QW All authors read and approved the final

manuscript.

Acknowledgements This study was supported by the funds from “China’s Thousand Talents Program ” Recruitment at Fudan University and by the Shanghai Committee

of Science and Technology, China (Grant No.12DZ2260100) We would like to thank Yu-Hu Xin and Hong-Yu Gu from FUSCC for the technical support.

Author details

1

Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.

2 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.3Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China 4 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.5Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

6

Department of Epidemiology, The University of Texas M.D, Anderson Cancer Center, Houston, Texas, USA.

Received: 15 August 2012 Accepted: 9 December 2012 Published: 15 January 2013

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doi:10.1186/1471-2407-13-19

Cite this article as: Shi et al.: A pri-miR-218 variant and risk of cervical

carcinoma in Chinese women BMC Cancer 2013 13:19.

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